Randomized Comparative Efficacy of Dexamethasone to Prevent Postextubation Upper Airway Complications in Children and Adults in ICU

Summary Prophylactic steroid therapy to reduce the occurrence of postextubation laryngeal edema is controversial. Only a limited number of prospective trials involve adults and children in an intensive care unit. The purpose of this study was to ascertain whether administration of multiple doses of dexamethasone to critically ill, intubated patients reduces or prevents the occurrence of postextubation laryngeal edema / stridor and its risk factors. Another specific objective of our study was to investigate whether an after-effect (that is, a transient lingering benefit) exists 24 hours after the discontinuation of dexamethasone In a prospective, randomized, double-blind control study, a total of 120 patients were randomly allocated both in children and adult population, who were ventilated more than 24 hours in ICU; into study and Control group. Study group comprising 60 patients with 30adults and 30 children. Study group adults received 8mg dexamethasone 4 doses i.e 4 hours prior to planned extubation, at extubation and 6 and 12 hours after extubation. Children received 0.5 mg.Kg−1 dose with maximum of 8mg at similar intervals. Control group comprising of 30 adults and 30 children who received placebo or saline at similar intervals. There was statistically significant difference (p = 0.019) in comparison of failed extubation (those who cannot withstand extubation and reintubated) in children with respect to adults. Moreover, duration of intubation (p =0.014) and female gender were also risk factors for failed extubation. We concluded that prophylactic use of intravenous dexamethasone is useful in preventing postextubation laryngeal edema/stridor in children but not in adults.


Introduction
Endotrachealintubation is a routine maneuver in Intensive Care Unit used to provide a patent airway and various modes of positive pressure ventilation in critically ill patients. 1 Laryngotracheal injury related to intubation may cause narrowing of the airway due to edemaof theglottis. Laryngealedema ismore common after endotrachealintubation for more than 36 hours 1 . Edema in this regionis associatedwith theincreased risks for postextubation stridor, which increase reintubation rate, a process referred to as failed extubation.
Reintubation may result in morbidity and mortality [2][3][4][5][6] . Prolonged intubation or excessive endotracheal tube cuff pressure can initiate mucosal erosion and cartilage necrosis followed by tracheal stenosis. 2 Mortality associated with reintubation has been estimated to be as high as 30% to 40% 4,6 . Because the presence of an endotracheal tube (ETT) precludes direct visualization of theupper airway,recognition ofthe edemadue to laryngotrachealinjury isoften difficult be as high as 30% to 40% 4,6 The prevalence of postextubation stridor ranges between 6% and 37% in intubated patients [7][8][9][10][11][12] Factors that may increase the likelihood of airway damage include repeated passage of endotracheal tube, prolonged intubation for more than 24-hours and a large size of endotrachealtube in relation to the size of the glottis, low Glasgow Coma Scale score, and fe-male sex. Female sex is at a higher risk of developing complications probably because of smaller size of larynx in comparison to males. 13,14 Mucosalmembrane in males tends to be more resistant to trauma. 15 Cervical flexion and extension, inspiration, cough and deglutination can all affect the relative position of larynx and endotrachealtube. Dynamic interactions may cause injury either by alternations in pressure on the mucosa or by frictional erosion 16 . Radiographic examination hasshown thatendotrachealtubecan move 3.8 cm when head is movedfrom flexionto extension. 17 .
Laryngeal edema is most commonly symptomatic in children becauseof their small airway size, more severely reduced in cross-sectional area by edema. Reactive subglottic edema in children at the cricoid ring can lead to post extubation stridor. 18 Laryngeal edema has been reported after tracheal extubation as one of the serious complications and causes significant morbidity as well as prolongs the stay in ICU. Pre-extubation dexamethasone therapycould prevent the complications of prolonged intubation which becomes obvious at the time of extubation. By reducingthe degree of laryngealedema, corticosteroids may reduce the incidence of reintubation orfailed extubation, which has clinical, economical and ethical problems in patients admitted in ICU. 9,10 Controversy stillexists regardingthe effectiveness of prophylactic steroid therapy for patients at risk for postextubation stridor [19][20][21][22] . Some studies involving postextubation stridor and analyses of outcomes for thosereceiving steroids duringintubation have yielded inconclusive or negative results 19 . Only a limited number of randomized trialsinvolving adults and evaluating the benefits of corticosteroid therapy prior to extubation have been conducted 21,22 . Moreover, studies regardingthe efficacy of prophylactic corticosteroids for intubated patients have yielded conflictingresults due to differences in the number of doses, types of corticosteroids, and timingand methods of administration to adult patients.
In ourclinicalpractice,the plannedextubation was usually performed four hour after the first injection of multiple prophylactic doses of dexamethasone .Sometimes, due to unpredictable conditions, critically ill patients need to delay the planned extubation after steroid treatment.Previous studiesreported thatmost highrisk patients susceptible to postextubation upper airway edema who fail extubation require reintubation within 48 to 72 hours 3,23 . However, little is known about the after-effect of multiple-dose dexamethasone to prevent postextubation stridor The present study aims to determine the role of intravenousdexamethasone inpreventingpostextubation laryngealedema/ stridorin adults and childrenwho were undergoingtheir first elective extubation in anICU. The specific objectives of our study were to determine whethermultiple doses of dexamethasone are effective to reduce or prevent postextubation airway obstruction and to investigate whether an after-effect (that is, a transient lingering benefit) exists 24hours after the discontinuationof dexamethasone.

Methods
A total of 120 pediatric and adult patients who were admitted to the medicalICU between Jan 2003to Feb 2006 were included in the study as approved by our localethical committee. This was prospective, randomized, double blind, placebo-controlled study. After obtaininginformed consent from the patientsor their relatives, stratified random sampling was employed to select adults and children in 1:1 ratio among patients fulfilling eligibility criteria. The patients were then randomized in each group separately to receive either Dexamethasone or Placebo. The procedure adopted was permuted block randomization in order to keep equalnumbers in each group.
The patients who were on ventilators (Puritan bennett840) for more than 24 hours were studied in ICU. All intubations were performed by a qualified experienced Anaesthetist in the operating room or in AccidentalEmergency. Tracheawas intubated with the standard endotrachealtube size according to their age. Children less than 10 yrswere intubated with uncuffed endotrachealtube. Allpatients requiringprolonged intubation and mechanical ventilation were sedated or paralyzed accordingto individualneed to prevent agitation and excessive movement of the endotracheal tube, or interference with the ventilator. Routine nursing careincluded ETTsuctioningeverytwo hoursand as needed to maintaina patent airway. Theadmitting diagnosis ranged from postoperative recovery to trauma.

5.A history of extubation during the same hospitalization
In our study, patients were randomly assigned to two groups:-Study group and Control group.
1. Study Group comprising 60 patients with 30 adults and 30 children. In adults dexamethasone 8mg bolus i.v. was given 4 hours prior to planned extubation, at extubation and at 6 and 12 hours after extubation.
2. Control Group:-comprising 30 adults and 30 children who received placebo or saline at similar intervals.
The dexamethasone and the placebo were prepared in identical volume and labeled as A and B in a syringe to ensure administration in double blind fashion; neither the intensivist ordering the drugs nor the person administering them was aware of the drugs being given to the patient till the end of the study.
Endotrachealextubations were followed according to standard ICUweaning protocol(ventilators used were Puritan Bennett 840 touch screen) as under: -(a) Temperature of less than or equal to 38°C for more thaneight hours, (b) Discontinuous use of sedatives, (c) Heart rate of more than or equal to 70 beats per minute and less than or equal to 130 beats per minute, (d) Systolic blood pressure (SBP) of more than or equal to 80 mm Hg in the absence of vasopressor, (e) Fraction of inspired oxygen (FiO 2 ) of less than or equal to 60%, partial pressure of oxygen (PaO 2 ) of more than or equalto 60mm Hg, and PaO 2 /FiO 2 ratio of more than 200, (f) Positiveend-expiratory pressure(PEEP) ofless than or equal to 5 cm H 2 O, (g) Respiratory rate = < 40/min (h) Minute ventilation of less than or equal to 15 liters perminute, and (i) pH of more than or equal to 7.3. (j) Static Compliance (CST) > 33ml/cm H2O Supplementaloxygen was continued to maintain an oxygen saturation of more than 95% as measured by a pulse oximeter.
All patients were clinically assessed for stridor, laryngeal edema (postextubation obstruction) after extubation for up to 24 hrs. The person assessing the parameters was unaware of the drug the patient had received. The patients with respiratory distress were assigned to take non-invasive positivepressure ventilation (bi-level positive airway pressure Puritan Bennett USA) by face mask if they failed in response to two doses of epinephrine inhalation and exhibited at least two of the following criteria of respiratory distress: (a) respiratory acidosis (defined as an arterial pH of less than 7.35 with a partialpressure of arterial carbon dioxide of more than 45 mm Hg), (b) Clinical signs suggestive of respiratory-muscle fatigue or increased respiratory effort (that is, use of accessory muscles, intercostal retraction, or paradoxical motion ofthe abdomen), Patients were reintubated with mechanical ventilation support if they met at least one of the following criteria: (a) A pH of less than 7.3 with a partial pressure of carbon dioxide increase of more than 15mm Hg, (b) Achange in mental status rendering the patient unable to tolerate non-invasive ventilation, (c) A decrease in the oxygen saturation to less than 85% despite the use of a high FiO 2 (a PaO 2 of less than 50 mm Hg with an FiO 2 of more than 70%), (d) Lackof improvement in signsof respiratory-muscle fatigue, (e) Hypotension with an SBP of less than 80 mm Hg formore than 30 minutesdespite adequatevolume challenge, (f) A diastolic blood pressure drop of more than 20 mm Hg, or (g) Copious secretions that could not be cleared adequately or that were associated with acidosis, hypoxemia, or changes in mental status (somnolence, agitation, or diaphoresis).

Statistical analysis
Baseline characteristics were compared in both groups; ascertain comparability by using appropriate statistical tests.Chi-squaretest ( 2 )and Fisher'sexact't' test were used to evaluate difference in categorical data while unpaired't' test was used to evaluate statistical significance inmean values.
All analysis was performed by using computer software SPSS ver. 10.0 for windows and p-value of < 0.05 was considered of statistical significance.

Results
Followingobservations were made in our study:-1. There was no statistically significant difference (p>0.05) among the groups in respect of age, sex, admittingdiagnosis, ICUstay, intubation type and duration of intubation. (Table 1,2,3,4) 2. There was statistically significantdifference (p = 0.019) in comparison of failed extubation in children    with respect to adults. InDexamethasone group, in children 30% cases were of failed extubation whilein control group, it was 63.33%. (Table 5).
3. On comparison between duration of intubation with incidence of failed extubation in adults in Dexa group, we found that with duration of intubation > 72 hours, failed extubation incidence was high with statistical significance (p=0.014). Similarly in Controlgroup, incidence of failed extubation with respect to duration of intubation was statistically significant (p = 0.028). In children, in Dexamethasone group, the incidence of failed extubation with duration of intubation less than 72 hours was 22.22% whileduration ofintubation more than 72 hours was 41.67%. This difference although more with longer duration of intubation (more than 72 hours) but was statistically insignificant. (Table 6) 4. There was statistically significant variation on comparison of failed extubation/laryngealedema incidence with that of sex. In Dexamethasone group, in adults 72.73%females had laryngeal edema which was statistically significant (p = 0.035). While in Control group, 70.59% females had failed extubation/ laryngealedema.Although females had significant high incidence of failed extubation/laryngeal edema in Control groupbut did not reach statisticalsignificance. (Table 7). 5. Only inchildren betweentwo groups,there was highly statistical significance in Airway assessment status (p = 0.004). Laryngeal edema was more in Control group (63.33%) in children as compared to Dexamethasone group (26.67%). While in adult patients there   was an equivocal response in incidence of failed extubation/laryngealedema betweentwo groups. (Table 8)

Discussion
The potentialbenefit ofsteroids tolaryngealedema is presumably based on its anti-inflammatory actions, which inhibitthe releaseof inflammatorymediators and decrease capillary permeability. The risk of harm from steroid therapy for 24 hours or less to prevent postextubation laryngeal edema is negligible [21][22][23] The extent of the effect of prophylactic steroids on airway obstruction is still a matter of some controversy.
We conducted this randomized clinical trial to evaluate the effects of prophylactic dexamethasone therapy inpreventinglaryngealedema foradult patients and children in ICU setting. The choice of dexamethasone wasbased on its highanti-inflammatory potency, negligiblemineralcorticoideffects attherapeutic doses, and long duration of action 24 . We investigated the after-effect until24 hours after the last dose of dexamethasone.
The incidence of laryngeal edema/stridor in our study, after extubation patient population has been reported to range from 26.67-36.67% which are not comparable toreports in literature rangingfrom 3-22%. 1,10 This higherincidence oflaryngeal edema and stridor is found to be associated with by many authors 2,3,7 These results in literature, however, were obtained in studiesevaluating shortterm operativeintubations; these studies did not include patients with wide spectrum of diagnosis& prolonged period of intubation as is practiced in our study.
The increased incidence of laryngealedema may be due to the fact that our study intended to select patients who required longer duration ofintubation more than 24hours and because of logistic concerns (4 doses of dexamethasone).
Our findings of steroid effect in reducing postextubation stridor wereconsistent with the results of the two recent studies in adult medicaland surgical ICU settings 21,22 . In a recent study with a large number of subjects, Francois and colleagues 22 reported that four doses of 20 mg of methylprednisolone, given at four hour intervals, significantly reduced the incidence of postextubation stridor from 22%to 3%and reduced the incidence of reintubation from 8% to 4%. However, the subjects in this study were not restricted to thehigh-risk patientsfor postextubationlaryngealedema (unlike the subjects in our study). The reduction of postextubation stridorin ourstudy was statistically significant, butnot asdramatic asthat ofthe studyof Cheng and colleagues 21 . Another reason for this discrepancy may be the difference in thetiming ofextubation. Cheng and colleagues executed the extubation one hour after methylprednisoloneadministration over the span of 24 hours. The after-effectof dexamethasone validates the reduced incidence of postextubation stridor after multiple doses of dexamethasone.
The development of stridor is unpredictable and this type of acute upper airwayobstruction canbe characterized by range of symptoms rangingfrom hoarsenessto severeobstruction requiringreintubation. Moreover, female sex is also riskfactor for laryngeal edema identified in our study. Several authors have also stressed female gender as risk factor. 11-13. Our study results are in agreement with studies 1,10,14-16 who concluded that postextubation stridor was reduced in chil-dren with prophylactic administration of dexamethasone, but in adults, it didnot appear to reduce the need for reintubation.
Our results are contradictory to the studies done by Gaussorgues P 11 , Courtney 17 , Tellez D 18 who demonstrated thatincidence of laryngeal edema/stridor was not modified bycorticosteroids (Dexamethasone).
Our study have substantiatedthat corticosteroids confer the benefits in children at high risk for postextubation laryngeal edema,whereas aroutine prophylactic use of corticosteroids to preven t postextubation stridorin every intubated patient is unwarranted. Dexamethasone and other steroids, in appropriate doses, can be helpful in alleviating laryngeal edema in intubated high-riskpatients susceptible to airway obstruction, such as those requiring repeated or prolonged intubations.
Basedon this information,clinicians should consider initiatingprophylacticcorticosteroid therapy in this population. However, further studies areneeded to establish the optimaldosing regimens as wellas thesubgroupsof patientsat high risk forpostextubation laryngeal edema who will derive the greatest benefit from this preventive steroid therapy.